Effect of d-fenfluramine and 5,7-dihydroxytryptamine on the levels of tryptophan hydroxylase and its mRNA in rat brain.

Abstract Repeated high doses of d-fenfluramine (dF; 10 mg/kg, i.p. twice daily for 4 days) markedly reduced serotonin (5-HT) concentrations in the hippocampus and striatum of rat brain up to 1 month after treatment, while tryptophan hydroxylase (TPH) levels were reduced only in the hippocampus 5 days after injection. Unlike dF, an intracerebroventricular (i.c.v.) injection of 5,7-dihydroxytryptamine (5,7-DHT 150 μg/20 μl) induced a marked and long-lasting reduction of 5-HT and TPH in both brain regions. Thirty days after injection, 5,7-DHT, but not dF, markedly reduced the number of labelled neurons in the dorsal and ventral regions of the nucleus raphe dorsalis (NRD) and raised the levels of TPH mRNA in the spared neurons at all times examined. TPH mRNA levels were raised 5 and 15 days after dF treatment in the NDR suggesting that changes in the TPH gene expression or transcript stability result following 5-HT depletion. These data are in agreement with the suggestion that 5,7-DHT damages 5-HT nerve terminals and perikarya, but leave unanswered the question of the mechanism of the long-lasting reduction of 5-HT levels caused by high, repeated doses of dF.